Abstract 168: Response Gene to Complement 32 Suppresses Adipose Tissue Thermogenic Genes through Inhibiting Beta3 Adrenergic Receptor mTORC1 Signaling

Our previous study have shown that response gene to complement 32 (RGC-32) deficiency (Rgc32-/-) protects mice from diet-induced obesity and increases thermogenic gene expression in adipose tissues. However, the underlying mechanisms by which RGC-32 regulates thermogenic gene expression remain to be determined. In the present study, we found that RGC-32 expression in white adipose tissue (WAT) was suppressed during cold exposure-induced WAT browning. Rgc32-/- significantly increased thermogenic gene expression in the differentiated stromal vascular fraction (SVF) of inguinal WAT (iWAT). Interestingly, Rgc32-/- and cold exposure regulated a common set of genes in iWAT as shown by RNA sequencing data. Pathway enrichment analyses showed that RGC-32 deficiency downregulated PI3K/Akt signaling-related genes. Consistently, Akt phosphorylation was also decreased in Rgc32-/- iWAT, which led to an increase in β3-adrenergic receptor expression and subsequent activation of mTORC1. β3-adrenergic receptor antagonist SR 59230A and mTORC1 inhibitor rapamycin blocked the Rgc32 deficiency-induced thermogenic gene expression in iWAT both in vitro and in vivo. These results indicate that RGC-32 suppressed iWAT thermogenic gene expression through down-regulation of β3-AR expression and mTORC1 activity via a PI3K/Akt-dependent mechanism.